This proposed study will build upon the extensive epidemiologic database and specimen repository derived from an ongoing lung cancer case/control study "Ecogenetics Study of Lung Cancer" (R01 CA55679, PI: M. Spitz) designed to identify inter-individual differences in susceptibility to tobacco-induced lung carcinogenesis. Recent evidence has suggested that 1) sensitivity to benzo[a]pyrene diol epoxide (BPDE), the metabolic product of benzo[a]pyrene (B[a]P), constituent of tobacco smoke, is a constitutional phenomenon and is a risk predictor for lung cancer; 2) 3p deletion, a common chromosome defect in lung cancer, occurs more frequently in lung tumor tissues of smoking than nonsmoking patients; 3) elevated levels of in vitro BPDE-induced chromosomal damages in peripheral blood lymphocytes (PBLs) at 3p21.3 and 3p21 are associated with risk of lung and other smoking-related cancers; and 4) a novel genetic locus on chromosome 6q 23-25 predisposes increased risk for lung cancer in families with multiple relatives affected with lung cancer. Therefore we propose to extend these findings using the detailed family history data and stored cell suspensions from the parent grant to further elucidation of the molecular targets of BPDE as lung cancer susceptibility loci. We will identify 400 lung cancer patients (200 cases with a positive family history for lung cancer in at least one first degree relative and 200 sporadic cases with no family history of lung cancer) and 200 controls (matched to the sporadic lung cancer cases on sex, age (+/-5 years), smoking, ethnicity and date of enrollment (+/-2 months). Specifically we propose: 1). To determine, using fluorescent in situ hybridization (FISH) techniques, whether BPDE-induced chromosomal aberrations on 3p21.3, 6q23-25 and 9p21 are more common in the cultured peripheral blood lymphocytes (PBLs) of lung cancer patients than controls. Outworking hypothesis is that exposure to in vitro BPDE may preferentially target specific loci and that lung cancer cases will exhibit higher numbers of aberrations than controls. 2). To determine whether BPDE-induced chromosomal aberrations on 3p21.3, 6q23-25 and 9p21 are more common in the lymphocytes (PBLs) of cases with familial lung cancer compared to sporadic lung cancer cases. Our working hypothesis is that aberrations in PBLs are associated with inherited susceptibility and in turn associated with familial lung cancer. 3). To assess the associations between the higher levels of induced aberrations and age, sex, and known environmental and occupational exposures by integrating epidemiologic data with the molecular cytogenetic data. Our hypothesis is that higher levels of BPDE-induced 3p21.3, 6q23-25 and 9p21 aberrations in PBLs are attributed to global genetic instability and their effect on lung cancer risk is independent of other exposures. These data are being routinely collected in the parent grant. These proposed susceptibility markers may be useful as biomarkers to identify high-risk populations that could then be targeted for intensive smoking-cessation programs and could be enrolled into chemoprevention screening trials. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]